Nuclear and extranuclear effects of vitamin A

Abstract

Vitamin A or retinol is a multifunctional vitamin that is essential at all stages of life from embryogenesis to adulthood. Up to now, it has been accepted that the effects of vitamin A are exerted by active metabolites, the major ones being 11-cis retinal for vision, and all trans-retinoic acid (RA) for cell growth and differentiation. Basically RA binds nuclear receptors, RARs, which regulate the expression of a battery of target genes in a ligand dependent manner. During the last decade, new scenarios have been discovered, providing a rationale for the understanding of other long-noted but not explained functions of retinol. These novel scenarios involve: (i) other nuclear receptors such as PPAR β/δ, which regulate the expression of other target genes with other functions; (ii) extranuclear and nontranscriptional effects, such as the activation of kinases, which phosphorylate RARs and other transcription factors, thus expanding the list of the RA-activated genes; (iii) finally, vitamin A is active per se and can work as a cytokine that regulates gene transcription by activating STRA6. New effects of vitamin A and RA are continuously being discovered in new fields, revealing new targets and new mechanisms thus improving the understanding the pleiotropicity of their effects.

RDH10-mediated retinol metabolism and RARα-mediated retinoic acid signaling are required for submandibular salivary gland initiation

“…It is the active metabolite of retinol, also known as vitamin A, and is essential for the morphogenesis of many organs and structures during embryonic development (Clagett-Dame and DeLuca, 2002;Duester, 2008;Metzler and Sandell, 2016;Niederreither and Dollé, 2008). RA has multiple modes of action, including nuclear functions and roles outside the nucleus (Al Tanoury et al, 2013;Iskakova et al, 2015). 'Canonical' RA signaling involves RA within the nucleus functioning as a ligand modulating the action of nuclear receptor transcription factors, specifically, members of the RAR family (RARα, RARβ and RARγ) and peroxisome proliferation-activated receptor (PPAR)-β/δ (Berry and Noy, 2009;Schug et al, 2007).…”

Genetic Variations Associated with Vitamin A Status and Vitamin A Bioavailability

“…VA plays a critical role as a signaling molecule in most tissues [76,77] and chromophore in eyes [2,3,4,5]. The metabolism of VA in extra-hepatic tissues is assumed to involve pathways like those present in the liver, e.g., RET is assumed to give retinal, then retinoic acid; βC is assumed to be cleaved into retinal and/or apocarotenals, although some differences do exist.…”

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

“…Also, in this case, the molecular mechanism of these rescue events remains to be elucidated. Retinoic acid signaling functions by directly regulating gene expression (Bar‐El Dadon & Reifen, ; Iskakova, Karbyshev, Piskunov, & Rochette‐Egly, ; le Maire & Bourguet, ) and as a result, abnormal retinoic acid signaling most probably induces changes on the normal epigenetic pattern.…”